WO2003103676A2 - Methode destinee a traiter le cancer au moyen d'inhibiteurs des kinases - Google Patents

Methode destinee a traiter le cancer au moyen d'inhibiteurs des kinases Download PDF

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WO2003103676A2
WO2003103676A2 PCT/US2003/017565 US0317565W WO03103676A2 WO 2003103676 A2 WO2003103676 A2 WO 2003103676A2 US 0317565 W US0317565 W US 0317565W WO 03103676 A2 WO03103676 A2 WO 03103676A2
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kinase inhibitor
resistance
cancer
kinase
surmounting quantity
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WO2003103676A3 (fr
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David B. Agus
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Cedars-Sinai Medical Center
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Priority to DK03734386T priority Critical patent/DK1509230T3/da
Priority to JP2004510795A priority patent/JP2005529162A/ja
Priority to BR0311814-2A priority patent/BR0311814A/pt
Priority to AU2003238871A priority patent/AU2003238871B2/en
Priority to DE60310922T priority patent/DE60310922T2/de
Priority to EP03734386A priority patent/EP1509230B1/fr
Priority to SI200330623T priority patent/SI1509230T1/sl
Priority to CA002487983A priority patent/CA2487983A1/fr
Priority to MXPA04012129A priority patent/MXPA04012129A/es
Publication of WO2003103676A2 publication Critical patent/WO2003103676A2/fr
Publication of WO2003103676A3 publication Critical patent/WO2003103676A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Embodiments of the present invention are directed to methods for treating and preventing disease conditions, such as cancer, particularly in those individuals who have developed a resistance or who are not responsive ab initio to tyrosine kinase inhibitor (TKI) therapy.
  • TKI tyrosine kinase inhibitor
  • RTKs Ligand-mediated receptor tyrosine kinase inhibitors
  • Approximately sixty such RTKs have been identified to date; their respective cell signaling pathways having been studied in detail.
  • misregulation of RTK signaling pathways has been observed in various types of human cancer, suggesting that signal transduction therapy may be a useful therapeutic modality for the treatment of cancer.
  • GLEEVEC Philadelphia chromosome positive (Ph+) chronic myeloid leukemia
  • a promising set of targets for therapeutic intervention in the treatment of cancer includes the members of the HER-kinase axis. They are frequently upregulated in solid epithelial tumors of, by way of example, the prostate, lung and breast, and are also upregulated in ghoblastoma tumors.
  • Epidermal growth factor receptor (EGFR) is a member of the HER-kinase axis, and has been the target of choice for the development of several different cancer therapies.
  • EGFR tyrosine kinase inhibitors are among these therapies, since the reversible phosphorylation of tyrosine residues is required for activation of the EGFR pathway.
  • EGFR-TKIs block a cell surface receptor responsible for triggering and/or maintaining the cell signaling pathway that induces tumor cell growth and division. Specifically, it is believed that these inhibitors interfere with the EGFR kinase domain, referred to as HER-1.
  • EGFR-TKIs are three series of compounds: quinazolines, pyridopyrimidines and pyrrolopyrimidines.
  • IRESSA Gefitinib
  • TARCEVA Erlotinib
  • Conventional prostate cancer treatment with both IRESSA and TARCEVA involves the daily, oral administration of no more than 500 mg of the respective compounds.
  • IRESSA became the first of these products to reach the United States market, when it was approved for the treatment of advanced non-small cell lung cancer patients.
  • IRESSA is an orally active quinazoline that functions by directly inhibiting tyrosine kinase phosphorylation on the EGFR molecule. It competes for the adenosine triphosphate (ATP) binding site, leading to suppression of the HER-kinase axis.
  • ATP adenosine triphosphate
  • a significant limitation in using these compounds is that recipients thereof may develop a resistance to their therapeutic effects after they initially respond to therapy, or they may not respond to EGFR-TKIs to any measurable degree ab initio. In fact, only 10-15 percent of advanced non-small cell lung cancer patients respond to EGFR kinase inhibitors. Thus, although the compounds may, at first, exhibit strong anti-tumor properties, they may soon become less potent or entirely ineffective in the treatment of cancer. Moreover, since medical research has heretofore not elucidated the biomolecular or pathological mechanism responsible for this resistance, patients who have exhibited such resistance to date have been left with few therapeutic alternatives to treat their disease. For patients that develop resistance, this potentially life-saving therapeutic mechanism did not achieve what they had hoped for and so simultaneously needed ⁇ an active therapy for cancer.
  • Embodiments of the present invention provide a therapy for the treatment of disease conditions, such as cancer, and, in particular, for the treatment of cancer in individuals who have developed a resistance to conventional TKI therapy or who are not responsive thereto ab initio.
  • Described herein is a method that is surprisingly effective in treating cancer, and especially prostate, breast, lung, ovarian, brain and colon cancers, after such a resistance manifests or in patients who are not responsive to conventional TKI therapy; dramatically hindering or even reversing the progression of this disease.
  • the method includes administering to patients a resistance-surmounting quantity of a TKI, which may be administered with less frequency than conventional TKI treatments.
  • this variant treatment regimen effectively blocks different members of the HER-kinase family.
  • Standard dosing of a TKI is effective at blocking activation of EGFR, but intermittent, increased dosages of a TKI may block HER-2, as well as EGFR; thereby effecting a clinical benefit ⁇ i. e. , tumor responses) in patients that do not respond to standard daily dosing of a TKI.
  • EMP-1 epithelial membrane protein- 1
  • Figure 1 depicts a graphical comparison (including mathematical standard error) of bolus dosing (lg/kg) of a TKI (IRESSA) once per week compared with dosing of the same TKI five times per week in a conventional dosing regimen in accordance with an embodiment of the present invention.
  • a control ⁇ i.e., no TKI administered
  • This experiment was performed in an androgen-independent prostate xenograft model. Equivalent growth inhibition was seen with daily or bolus dosing. The daily dosing was at the maximally tolerated dosage in the mice.
  • Figure 2 depicts a graphical comparison (including mathematical standard deviation) of bolus dosing (lg kg) of a TKI (IRESSA) once per week compared with dosing of the same TKI five times per week in a conventional dosing regimen in accordance with an embodiment of the present invention.
  • a control ⁇ i.e., no TKI administered
  • This experiment was performed in an androgen-independent prostate xenograft model. Equivalent growth inhibition was seen with daily or bolus dosing. The daily dosing was at the maximally tolerated dosage in the mice.
  • Figure 3 depicts a graphical comparison of subcutaneous xenograft tumor volume in animals treated with a TKI (IRESSA) as opposed to control animals that received no TKI therapy in accordance with an embodiment of the present invention.
  • Figure 4 A depicts a scheme to develop two separate IRESSA-resistant (IR) tumor lines (CWR22R, CWRS A6) by serially passaging tumors in accordance with an embodiment of the present invention.
  • Figure 4B depicts a graphical representation of an IRESSA resistance challenge in accordance with an embodiment of the present invention. IR tumors treated with IRESSA exhibited growth similar to untreated parental tumors.
  • Figure 5 depicts a graphical representation of IR tumors treated with the monoclonal antibody 2C4 (available from Genentech, Inc.; hereinafter "2C4"), and showing an 81% growth inhibition as compared to IR tumors receiving IRESSA therapy in accordance with an embodiment of the present invention. Additionally, tumors treated with a combination of IRESSA and 2C4 resulted in a similar tumor growth curve as 2C4 alone (statistically insignificant difference).
  • Figure 6 A illustrates the ability of EGF to activate MAPK to equivalent levels in both
  • Figure 6B illustrates IRESSA inhibition of p-MAPK on IR cells stimulated with TGF- ⁇ in accordance with an embodiment of the present invention.
  • Figure 6C illustrates the direct effect of IRESSA on p-EGFR in accordance with an embodiment of the present invention.
  • Figure 7 A illustrates that total EGFR protein remained unchanged in IR tumors in accordance with an embodiment of the present invention.
  • Figure 7B illustrates that EGFR and HER-2 mR A remained unchanged in IR tumors in accordance with an embodiment of the present invention.
  • FIG 8 depicts a case-by-case clinical response to TKI (IRESSA) therapy compared with patient EMP-1 expression level in accordance with an embodiment of the present invention.
  • This data is from patients with non-small cell lung cancer treated with IRESSA; their clinical response was correlated with EMP-1 expression level.
  • the probability of response to TKI (IRESSA) therapy was less than 10% in individuals whose EMP-1 expression level was above the threshold (i.e., dotted line) indicated (i.e., gene was "detectable” at the mRNA or protein levels, as assessed by TAQMAN technology).
  • Figure 9 depicts a graphical comparison of the probability of response to TKI (IRESSA) therapy against patient EMP-1 expression level in accordance with an embodiment of the present invention. This data is from patients with non-small cell lung cancer treated with IRESSA; their clinical response was correlated with EMP-1 expression level.
  • TKI therapies such as IRESSA and TARCEVA, as discussed above, are indicated for administration to patients in a daily regimen for the treatment of cancer at dosages intended to block activation of EGFR.
  • patients frequently develop a resistance to this treatment.
  • the present invention is based on the inventor's surprising discovery that a variant dosing regimen of a TKI may be administered to resistant patients to overcome their resistance, or to patients who are not responsive to TKI therapy ab initio to overcome their non-responsiveness (both indications are hereinafter included in the term "resistant" when used to describe individuals with cancer).
  • This dosing schedule is surprisingly well-tolerated; increased dosages of daily TKI are generally not well-tolerated.
  • Further embodiments of the present invention are based on the inventor's identification of EMP-1 as a gene responsible for this resistance or non-responsiveness.
  • the methods of the present invention are not limited to the treatment of cancer.
  • the biomolecular pathways addressed and the TKI resistance obviated by the methods of the present invention may find application in the treatment of other disease conditions; any disease condition in which treatment with a TKI would result in a beneficial result for a patient under treatment.
  • "Beneficial results” may include, but are in no way limited to, lessening the severity of the disease condition, preventing the disease condition from worsening, curing the disease condition and prolonging a patient's life or life expectancy.
  • These disease conditions may relate to or be modulated by EGFR, HER-2 kinase or any other kinase that may be clinically affected with the methods of the present invention.
  • the inventor's experimental studies have demonstrated clinical activity of TKIs at the daily dosing regimens in his xenograft models, and molecular studies on these tumors demonstrated effective inhibition of the EGFR signaling cascade. This confirmed that the xenograft models properly reflected the behavior of these TKIs as observed in other model systems.
  • the inventor also surprisingly demonstrated that weekly IRESSA dosages at an amount significantly greater than the recommended daily dosing was well tolerated and can inhibit tumor growth effectively in the xenograft models ⁇ even in tumors that demonstrated a resistance to conventional TKI therapy.
  • a once- or twice-weekly increased dosage of a TKI may be effective in treating cancer, and especially lung, breast and prostate cancer, in an individual who is resistant to conventional TKI therapy.
  • TKIs suitable for use in accordance with the methods of the present invention may include, but are in no way limited to, TKIs that are generally known for use in the treatment of cancer, and, specifically, breast, lung and prostate cancer.
  • TKIs may include IRESSA and TARCEVA, as described above, but may further include CI1033 (available from Pfizer Inc.), PKI166 (available from ovartis AG), GW2016 (available from GlaxoSmithKline), EKB569 (available from Wyeth), IMC-C225 (available from ImClone Systems Inc.
  • any TKI that blocks EGFRs e.g., HER-1) or any other HER family receptor ⁇ e.g., HER-2, HER-3, HER-4) may be utilized, since it is believed that the blocking of these EGFRs and other receptors is the biomolecular means by which TKIs function to hinder or prevent the growth of lung, breast and prostate tumors as well as tumors associated with other types of cancer.
  • a TKI may be administered to a patient with cancer who is resistant to conventional TKI therapy in a "resistance-surmounting quantity," which, for purposes of the present invention, is defined as an amount of from about 500 mg to about 3,000 mg, administered as a bolus once or twice per week.
  • the appropriate specific dosage of the TKIs of various embodiments of the present invention depends on the age and weight of the individual to be treated, whether the compound is being used as single agent or adjuvant therapy, the type of cancer ⁇ e.g., whether it is an adenocarcinoma, sarcoma, squamous cell carcinoma, ductal transitional carcinoma, or other prostatic cancer), the progression of the cancer ⁇ e.g., whether it has metastasized or is localized), the nature of the tumor(s) to be treated ⁇ e.g. , size, location, etc.) and other factors well known to those skilled in the art of oncology.
  • the type of cancer e.g., whether it is an adenocarcinoma, sarcoma, squamous cell carcinoma, ductal transitional carcinoma, or other prostatic cancer
  • the progression of the cancer e.g., whether it has metastasized or is localized
  • the nature of the tumor(s) to be treated e.g.
  • intermittent ⁇ i.e., weekly or semi- weekly doses of between about 500 mg and 3,000 mg may be used (depending on the particular TKI); doses of between about 1,500 mg and 3,000 mg are preferred for most cases; doses of about 2,000 mg are further preferred.
  • the administration of either IRESSA or TARCEVA at a single dose of about 2,000 mg per week may be especially effective.
  • the selection of an appropriate pharmaceutical TKI and an appropriate dosage can be readily performed by one of skill in the art.
  • the particular dosage may be selected to effect at least one of several internal biological conditions.
  • the dosage may be selected to block the HER-2 kinase, either in addition to or in lieu of blocking the HER-1 , or EGFR, kinase.
  • the dosage may be selected to yield a serum concentration of greater than about 800 ⁇ M of the TKI.
  • the dosage may be selected to block a kinase receptor other than EGFR or HER-2 to produce an anti- cancer treatment modality.
  • a dosage within the above-described range may effect at least one of these biological conditions; however, it will be readily understood by one of skill in the art that not all of these conditions must be satisfied for the methods of the present invention to be effective in the treatment of cancer.
  • a dosage outside the above-identified range that effects these biological conditions is considered to be within the scope of the present invention.
  • a particular route of pharmaceutical administration may necessitate the use of a dosage substantially outside the above-described range, yet if such a dosage effects the biological conditions described herein, it is considered to be within the scope of the present invention.
  • TKI compounds of the present invention may be administered orally, although one can also administer them by intravenous and intramuscular injection.
  • IRESSA or TARCEVA is administered orally in a bolus of about 2,000 mg once per week.
  • another embodiment of the present invention includes a diagnostic method for determining an individual's sensitivity to TKI therapy by screening their expression level of EMP-1.
  • An individual with a relatively higher expression level of EMP-1 is likely to be resistant or non-responsive or to develop a resistance or non-responsiveness to TKI therapy.
  • an individual with a relatively lower expression level of EMP-1 is less likely to be resistant or non-responsive or to develop a resistance or non- responsiveness to TKI therapy. This is graphically illustrated in Fig.
  • any conventional method known to those of skill in the art may be utilized.
  • TAQMAN quantitative PCR of frozen tissue to look for RNA expression
  • TAQMAN quantitative PCR of RNA extracted from paraffin blocks to look for RNA expression
  • immunohistochemistry of paraffin sections stained with labeled antibodies to EMP-1 to look for protein expression.
  • Figs. 1 and 2 each of which illustrate a comparison of dosing with 100 mg/kg IRESSA five times per week as compared with weekly bolus dosing with lg/kg IRESSA once per week (Fig. 1 includes standard error and Fig. 2 includes standard deviation information).
  • the Examples further describe a diagnostic method whereby an individual's expression level of EMP-1 is used to screen the individual's resistance to TKI therapy.
  • the Examples demonstrate the efficacy of the methods of the present invention with respect to androgen- ' independent prostate cancer xenografts, although similar experiments have been performed with respect to breast cancer, ovarian cancer and lung cancer xenograft models.
  • IRESSA targets the HER-kinase axis by competing for the ATP binding site on the EGFR molecule, as described above. It has previously been demonstrated to inhibit growth of epithelial cancer xenografts, including prostate tumors.
  • IRESSA 8-10 week old athymic nude mice bearing subcutaneous androgen-dependent (CWR22) or androgen-independent (CWR22R) xenograft tumors were administered a daily oral treatment of IRESSA at a dose of 100 mg/kg for three weeks. A significant reduction in tumor volumes was observed (Figs.
  • EXAMPLE 2 Development of an in vivo IRESSA-Resistant Model Having identified an androgen-independent prostate cancer model that is sensitive to IRESSA treatment, a corresponding IRESSA-resistant (IR) model was developed to evaluate the mechanisms of resistance with this drug. This was done by serially passaging IRESSA-treated CWR22R tumors in female athymic nude mice for twelve generations (Fig. 4A).
  • CWR22R tumors which first received IRESSA treatment at the initiation of the series, were termed "generation F0.”
  • Generation F0-F3 demonstrated sensitivity to IRESSA after three weeks of treatment (as evaluated by tumor growth curves); similar to that of the native CWR22R tumors.
  • generation F4 tumors demonstrated growth despite the presence of IRESSA.
  • the tumors were characterized as "resistant” after a challenge experiment showed IRESSA to be ineffective in inhibiting tumor growth on two independently derived IR lines as compared to the F0 parental tumors (Fig. 4B). Two separately derived, IR lines were developed.
  • 2C4 is a monoclonal antibody against HER- 2 that prevents its heterodimerization with HER-1, HER-3 or HER-4, and, consequently, inhibits tumor growth by ablating ligand-mediated signaling.
  • the IR tumors receiving 2C4 showed an 81% growth inhibition as compared to those receiving IRESSA (Fig. 5).
  • a combination of 2C4 and IRESSA resulted in a similar growth curve as 2C4 alone, suggesting that IRESSA was unable to potentiate the 2C4 effect.
  • IR CWR22R Tumor has Functional EGFR
  • p-MAPK phosphorylated mitogen activated protein kinase
  • tumor cells from both IRESSA-sensitive and IR tumors were cultured ex - vivo and starved of growth factors for 18-24 hours. They were then treated with a dose curve of either IRESSA or the vehicle, and stimulated with epidermal growth factor (EGF).
  • EGF epidermal growth factor
  • IRESSA inhibition of p-MAPK on IR cells was also evident on transforming growth factor- ⁇ (TGF- ⁇ )-stimulated cells (Fig. 6B); another ligand for EGFR.
  • TGF- ⁇ transforming growth factor- ⁇
  • p-EGFR phosphorylated-EGFR
  • EGFR protein remained unchanged in the IR tumors, as shown in Fig. 7A.
  • EGFR (HER-1) mRNA and HER-2 mRNA (the secondary target for IRESSA), also remained unchanged as determined by a real time quantitative reverse transcription polymerase chain reaction (RT- PCR) analysis (Fig. 7B).
  • EGFRvIII Another possibility for the resistance mechanism may have been the upregulation of the constitutively active EGFR class III variant, EGFRvIII.
  • EGFRvIII lacks 267 amino acids from its extracellular domain and has been reported in ghoblastoma multiforme, breast, ovarian, prostate and lung carcinomas. The likelihood of this molecule being upregulated in the IR model was small, because there is no evidence for regulation of EGFRvIII by EGF and TGF- ⁇ .
  • the ex vivo cells derived from the IR line clearly demonstrated ligand stimulation at the molecular level (Fig. 6A). Nevertheless, no difference in EGFRvIII expression changes between the sensitive and IR tumors were found by TAQMAN PCR analysis (data not shown).
  • MDR1 and MRPl The major multidrug transporters, MDR1 and MRPl, are involved in cancer drug resistance by extruding a large variety of hydrophobic compounds.
  • Overexpression of MDR1 was evaluated in the IR line both at the mRNA as well as the protein level. The expression of MDR1 in the IR tumor was equivalent to that in the sensitive tumor. Similar results were obtained when MDR1 was analyzed in the ex vivo cells derived from the respective tumors. In the xenograft model, the IR cells were still able to respond to EGF, as determined by the stimulation of MAPK; further supporting the absence of MDR1 overexpression. That this effect can be suppressed by.
  • IRESSA at a concentration equivalent to that for the sensitive cells argues against the presence of a drug efflux pump in the resistant cells.
  • the resistance mechanism of GLEEVEC has been a subject of intense study for the past few years. Although it is believed that the resistance mechanism may be multifactorial, one component of the resistance mechanism has been described as a point mutation (T315I) within the ATP-binding pocket of its target gene, BCR-ABL (Shah et al, Cancer Cell vol.2(2): 117-25 (2002)). This mutation was initially described in CML patients who had GLEEVEC-refractory disease or who had a relapse during the treatment (Roumiantsev et al., Proc. Natl. Acad. Sci. USA, vol. 99(16):10700-05 (2002)).
  • IRESSA is also a competitive inhibitor of ATP binding sites within the tyrosine kinase domains of EGFR and HER-2 (IC 50 for EGFR is ⁇ 0.015-0.05 ⁇ M and IC 50 for HER-2 is 1.2-3.7 ⁇ M), it was reasoned that resistance could be due to mutations within the kinase region of the target receptors required for IRESSA binding and, thus, inhibition.
  • the tyrosine kinase domains of both HER-2 and EGFR were sequenced using the sequencing primers set forth in Table 1.
  • EXAMPLE 8 Gene Expression Profiles of IR Tumors Reveals EMP-1
  • the gene expression profiles of IR tumors were analyzed by gene chip analysis, using the gene arrays described in Alon et al., Proc. Natl. Acad. Sci. USA, vol. 96(12):6745-50 (1999). Native tumors and tumors from generation F8 of both IR lines as well as native tumors treated with IRESSA for 12 hours were chipped. After statistical analysis, 96 genes were identified in the IR tumors as having changed more than 20-fold as compared to native tumors (data not shown). A strong correlation with lack of clinical response to IRESSA and presence of EMP-1 RNA was demonstrated (Fig. 8). Presence of EMP-1 RNA was assessed with TAQMAN from paraffin samples. Moreover, the probability of an individual responding to TKI therapy decreases as EMP-1 expression level increases (Fig. 9).

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Abstract

L'invention a trait à des méthodes destinées à traiter le cancer et d'autres maladies chez des personnes qui soit ont développé une résistance à la thérapie classique par inhibiteurs des tyrosines kinases (TKI), soit ne répondent pas, ab initio, à la thérapie classique par TKI. Dans divers modes de réalisation, les procédés consistent à administrer à un patient, de façon hebdomadaire ou bihebdomadaire, une dose dominant la résistance de TKI. D'autres modes de réalisation comprennent une méthode diagnostique destinée à évaluer la probabilité qu'une personne soit résistante à une thérapie par TKI, ladite méthode s'appuyant sur un niveau d'expression de la protéine-1 de la membrane épithéliale (EMP-1), qui est l'un des gènes considérés comme responsables de la résistance aux TKI. Les méthodes de la présente invention peuvent être particulièrement utiles pour le traitement de cancers du poumon, du sein, de la prostate, des ovaires, du cerveau et du colon. Les méthodes de la présente invention permettent de bloquer efficacement le domaine kinase HER-2, soit en plus, soit à la place, du domaine kinase EGFR.
PCT/US2003/017565 2002-06-05 2003-06-04 Methode destinee a traiter le cancer au moyen d'inhibiteurs des kinases WO2003103676A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DK03734386T DK1509230T3 (da) 2002-06-05 2003-06-04 Gefitinib ( IRESSA) til behandlingen af cancer
JP2004510795A JP2005529162A (ja) 2002-06-05 2003-06-04 キナーゼインヒビターを使用して癌を処置する方法
BR0311814-2A BR0311814A (pt) 2002-06-05 2003-06-04 Método de tratar câncer empregando inibidores de cinase
AU2003238871A AU2003238871B2 (en) 2002-06-05 2003-06-04 Method of treating cancer using kinase inhibitors
DE60310922T DE60310922T2 (de) 2002-06-05 2003-06-04 Gefitinib (iressa) zur behandlung von krebs
EP03734386A EP1509230B1 (fr) 2002-06-05 2003-06-04 Gefitinib (iressa) destinee au traitement du cancer
SI200330623T SI1509230T1 (sl) 2002-06-05 2003-06-04 Gefitinib (iressa) za zdravljenje raka
CA002487983A CA2487983A1 (fr) 2002-06-05 2003-06-04 Methode destinee a traiter le cancer au moyen d'inhibiteurs des kinases
MXPA04012129A MXPA04012129A (es) 2002-06-05 2003-06-04 Metodo para tratamiento del cancer utilizando inhibidores de cinasa.

Applications Claiming Priority (2)

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US38662202P 2002-06-05 2002-06-05
US60/386,622 2002-06-05

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WO2003103676A3 WO2003103676A3 (fr) 2004-03-25

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EP (3) EP1803821B1 (fr)
JP (1) JP2005529162A (fr)
KR (1) KR20050037510A (fr)
AT (2) ATE350039T1 (fr)
AU (1) AU2003238871B2 (fr)
BR (1) BR0311814A (fr)
CA (2) CA2590618A1 (fr)
DE (1) DE60310922T2 (fr)
DK (1) DK1509230T3 (fr)
ES (1) ES2279120T3 (fr)
MX (1) MXPA04012129A (fr)
PT (1) PT1509230E (fr)
SI (1) SI1509230T1 (fr)
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EP1837025A3 (fr) * 2002-06-05 2007-12-19 Cedars-Sinai Medical Center Procédé de traitement du cancer utilisant des inhibiteurs de kinase
EP1803821A3 (fr) * 2002-06-05 2007-12-26 Cedars-Sinai Medical Center Procédés de gestion de thérapie d'inhibiteurs de kinase
US7384940B2 (en) 2002-06-05 2008-06-10 Cedars-Sinai Medical Center Method of treating cancer using kinase inhibitors
WO2006008526A3 (fr) * 2004-07-23 2006-07-13 Astrazeneca Ab Procede
WO2006008526A2 (fr) * 2004-07-23 2006-01-26 Astrazeneca Ab Procede
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AU2006210572B2 (en) * 2005-02-03 2011-08-04 The General Hospital Corporation Method for treating gefitinib resistant cancer
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US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US9630946B2 (en) 2007-10-17 2017-04-25 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10035788B2 (en) 2007-10-17 2018-07-31 Wyeth Llc Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
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US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US10111868B2 (en) 2008-06-17 2018-10-30 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
WO2012135970A1 (fr) 2011-02-08 2012-10-11 Pontificia Universidad Catolica De Chile Inhibiteurs d'enzymes phosphohydrolase d'acide phosphatidique (pap) comprenant du d-propranolol et analogues, seuls ou combinés à de la désipramine, pour traiter des cancers qui dépendent du récepteur du facteur de croissance épidermique (egfr), ses variants oncogènes et autres membres de la famille des récepteurs tyrosine-kinases erbb/her

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MXPA04012129A (es) 2005-04-19
DE60310922D1 (de) 2007-02-15
ES2279120T3 (es) 2007-08-16
BR0311814A (pt) 2005-03-15
EP1837025A2 (fr) 2007-09-26
EP1803821B1 (fr) 2012-02-29
EP1803821A2 (fr) 2007-07-04
JP2005529162A (ja) 2005-09-29
SI1509230T1 (sl) 2007-06-30
KR20050037510A (ko) 2005-04-22
ATE350039T1 (de) 2007-01-15
AU2003238871A1 (en) 2003-12-22
US20070141621A1 (en) 2007-06-21
AU2003238871B2 (en) 2009-04-23
EP1837025A3 (fr) 2007-12-19
US20060134115A1 (en) 2006-06-22
EP1509230A2 (fr) 2005-03-02
EP1803821A3 (fr) 2007-12-26
DE60310922T2 (de) 2007-10-11
US7384940B2 (en) 2008-06-10
CA2487983A1 (fr) 2003-12-18
US20040001833A1 (en) 2004-01-01
ATE547708T1 (de) 2012-03-15
WO2003103676A3 (fr) 2004-03-25
PT1509230E (pt) 2007-03-30
EP1509230B1 (fr) 2007-01-03
US7803546B2 (en) 2010-09-28
CA2590618A1 (fr) 2003-12-18
DK1509230T3 (da) 2007-05-14

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